Dyslipidemia frequently accompanies type 1 diabetes (T1D) and represents an important component of the disease, imposing cardiovascular risk and correlating with renal dysfunction (1,2). Current clinical approaches directed towards diabetic dyslipidemia, including changes in lifestyle, stringent glycemic control, lipid lowering therapy, or combinations thereof, offer limited benefit, thus emphasizing the need for the development of novel therapies.
Therapy with statins reduces major cardiovascular events largely through reduction of low density lipoprotein (LDL) cholesterol (3). Still, an important residual cardiovascular risk, which is independent of LDL cholesterol levels, remains (4-8). Chylomicrons (CM), chylomicron remnants (CMR), and very low density lipoproteins (VLDL), cumulatively known as triglyceride-rich lipoproteins (TRL), contribute significantly to postprandial lipemia (9). Increased TRL levels represent an important additional risk factor for atherosclerosis (10), particularly in subjects with diabetes or the metabolic syndrome (11).
Glucagon-like peptide 1 (GLP-1), an incretin hormone secreted in the small intestine, promotes post-prandial insulin release, thereby reducing blood glucose levels (12). Endogenous GLP-1 also reduces postprandial glucagon secretion through direct actions on pancreatic islet cells, thus diminishing hepatic glucose output (13). GLP-1 analogs are used in the treatment of type 2 diabetes (T2D), leading not only to improvements in glycemic control, but also to reductions in chylomicron biogenesis, systemic inflammation and endothelial dysfunction (14-16). However, in T1D patients, a progressive elevation of postprandial glucagon, along with GLP-1 and plasma glucose, has been observed (17), suggesting impaired GLP-1 signaling or, alternatively, the presence of other dominant pathways blunting GLP-1 pathways.
Hypersecretion of growth hormone (GH) has been demonstrated to impair metabolic control in T1D patients by increasing circulating glucose and lipids (18-21). The release of GH by the pituitary is predominantly regulated by hypothalamic growth hormone-releasing hormone (GHRH). However, receptors for GHRH are also expressed in extra-pituitary sites and were shown to be independently involved in various physiological and pathological events (22-24). Whether the GHRH receptor is upregulated in the small intestine in the context of T1D, and whether its activation plays a role in the impairment of GLP-1 signaling and in the disease process, however, is still unknown.